Triamine acid addition salts in antifungal methods and compositions



United States Patent TRIAMINE ACID ADDITION SALTS IN ANTI- FUNGAL METHODS AND COMPOSITIONS Michael G. Mulinos, Westfield, N ..I., assignor to Commercial Solvents Corporation No Drawing. Continuation-impart of application Ser. No. 56,661, Sept. 19, 1960. This application Nov. 17, 1964, Ser. No. 411,702

17 Claims. (Cl. 167-58) This application is a continuation-in-part of US. patent application Ser. No. 56,661, filed Sept. 19, 1960, now US. Patent 3,164,619 of Jan. 5, 1965.

The present invention relates to a process for treating superficial fungus infections and to antifugal compositions, and more particularly it relates to such compositions containing acid addition salts of alkyl triamines, which salts possess antifungal activity, as the essential antifungal ingredient.

US. Patent No.-2,43-6,779 by Murray Senkus describes certain alkyl triamines including some of the compounds from which the instant acid addition salts are prepared. Similarly copending application Ser. No. 738,928 filed June 2, 1958, by John B. Tindall, now abandoned, describes applicable alkyl triamines.

In the past, many compounds have been discovered to have antibacterial activity, but comparatively few have been found to have antifungal activity permitting therapeutic use at practical levels. Further consideration must also be given to toxicity, especially the topical irritation and skin sensitization (allergenicity) frequency encountered in the use of prior antifungal agents.

Certain new compositions possessing practical antifungal activity which new compositions are essentially non-toxic when employed in amounts adequate to eradicate fungal infections caused by susceptible fungi have now been discovered. These compositions includes as their active, essential ingredient triamine acid addition salts such as defined in applicants copending application Ser. No. 56,661, filed Sept. 19, 1960, and now US. Patent 3,164,619, which have the followinggeneral formula:

wherein R consists of groups selected from the class consisting of hydrogen and methyl, with the proviso that if one R is methyl, then the other R must behydrogen; R consists of groups selected from the class consisting of propionic, caprylic, and undecylenic acids; and x is either 0 or 1, with the proviso that at least one x is 1.

Illustrative of. such triamine acid addition salts included in the above general formula are N ,2-dimethyl-N ,N bis (Z-ethylhexyl) 1,2,3 propanetriamine mono-propionate; N ,2-dimethyl N ,N bis(2-ethylhexyl)-1,2,3-propanetriamine dipropionate; N ,2-dimethyl N ,N bis(2- ethylhexyl)-1,2,3-propanetriamine tripropionate; N ,2-dimethyl-N ,N -bis(Z-ethylhexyl) 1,2,3 propanetriamine monocaprylate; N ,2 dimethyl-N ,N -bis(Z-ethylhexyl)- 1,2,3-propanetriamine dicaprylate; N ,2-dimethyl-N ,N bis(2 ethylhexyl) 1,2,3 propanetriamine tricaprylate; N ,2-dimethyl-N ,N -bis(2-ethylhexyl 1,2,3 propanetriamine mono-undecylenate; N ,2 dimethyl N ,N3-bis(2- ethylhexyl)-l,2,3-propanetriamine diundecylenate; N ,2- dimethyl-N ,N -bis( 2 ethylhexyl) 1,2,3 propanetriamine triundecylenate; N ,N bis(2-ethylhexyl) 2 methyl-1,2,3- propanetriamine mono-propionate; N ,N bis(2 ethylhexyl)-2-methyl-1,2,3-propanetriamine dipropionate; N N -bis(2-ethylhexyl.) .Z-methyl 1,2,3 propanetriamine tripropiona-te; N ,N -bis(2-ethylhexyl) 2 methyl-1,2,3- propanetriamine mono-caprylate; N ,N bis(2.- ethylhexyl)-2-methyl 1,2,3 propanetriamine dicaprylate;'N N -bis(2-ethylhexyl) Z-methyl 1,2,3 propanetriamine tricaprylate; N ,N -bis(2-ethylhexyl)-2-rnethyl 1,2,3-propanetriamine mono-undecylenate; N ,N bis'(2 ethylhexyl)-2-methyl 1,2,3 propanetriamine diundecylenate; N ,N '-bis(2-ethylhexyl) 2 methyl 1,2,3 propanetriamine triundecylenate and'the like.

In preparing the triamine acid addition salts, the corresponding'triamine havingthe following general formula wherein R-consists of groups-selected from the class consisting of hydrogen and methyl with the proviso that if one R is methyl, then the other R must be hydrogen, is reacted with propionic, caprylic or undecylenic acids. The triamine acid addition salts of my invention are prepared by mixing 1 mole of the corresponding triamine with 1, 2 or 3 moles of caprylic, propionic or undecylenic acid. Furthermore, mixtures of the three acids can be used. For instance, 1 mole of N ,N -bis(2-ethylhexyl)-2-methyl- 1,2,3-propanetriamine can be mixed with 1 mole of caprylic and 2 moles of undecylenic acid, or 1 mole of N N -bis(2-ethylhexyl) 2 -,methyl 1,2,3-propanetriamine can be mixedwith 2 moles of propionic acid, etc.

When utilizing N ,2-dirnethyl-N ,N -bis(2-ethylhexyl)- 1,2,3-propanetriamine, as the triamine starting material, it can be preparedaocording to the disclosure of copending application Ser. vNo. 738,928 filed June 2, 1958, by John B. Tindall. Whereas, vwhen utilizing -N ,N bis(2- ethylhexyl)-2-methyl-l,2,3propanetriamine, as the triamine starting material, it canbe prepared according to the disclosure of US. Patent No. 2,436,779.

The above compounds are uniquely suited for use as antifungal agents. For example, they can be incorporated in soaps and other suitable vehicles to enhance the nor- Generally, the compound will be present in the vehicle in amounts of at least about 0.1% by weight, preferably 0.5%, and although larger amounts may be used if desired, typically no more than about 5% by-weight of the compound isused.

The following examples further illustrate the present invention, but it is not intended that this invention be limited to the compounds, etc., set out therein. .Rather, it

is intended that equivalents obvious to those skilled in the art be included within the scope of the invention as claimed.

Example I The following table sets out the antifungal effects of compounds used in the instant invention. The compounds set out in Table I were found to inhibit completely the described organism at the described minimum inhibition concentration.

grams of ointment. Hydrophilic ointment (USP) is a water-removable ointment base having a formulation as follows:

Gm. Methylparaben 0.25 Propylparaben 0.15 Sodium lauryl sulfate 10.00 Propylene glycol 120.00 Stearyl alcohol 250.00

White petrolatum 250.00 Purified water 370.00

To make about 1000.00

Example IV A non-water washable therapeutic ointment can be prepared by mixing 0.5 to 5.0 grams of N ,N -bis(-2-ethylhexyl)-1,2,3-propanetriamine diundecylenate with enough petroleum white ointment (USP) to make 100 grams of ointment.

Example V A therapeutic aerosol spray for topical application can be formulated as follows:

Percent Fungicide of Example I 0.5-5 Dipropylene glycol 8-10 Isopropyl myristate 2-4 Menthol, about 0.05 Sufficient propellant (Freons) to make 100.0

Example VI A liquid cream therapeutic shampoo can be formulated as follows:

TABLE L-MI-NIMUM LNHIBITORY CONCENTRATIONS IN PARTS PER MILLION Test Organism Test Compound Aspergillus Candida Penicillium Fusarium niger albica'ns chrysogenum ozysporum N,z-dimethyl-N ,N -bis(Zcthylhexyl)-1,2,3-propanetriamine dipropionate 5004000 500-1000 10-100 10-100 N ,2-dirnethyl-N ,N -bis(2-othylhe l- 3- ropane triamine trifiropionate 1 -500 100-500 100-500 10-100 N ,2-dimethy -N ,N -bis(2-ethylhexy opanetriamine dieaprylate 500-1000 500-1000 100-500 10-100 N ,Z-dimethyl-N ,N -bis(2-ethylhexyl)-1,2,3-propanetriamine tricapryl e 100500 100-500 10-100 10-100 N ,N -bis(Z-ethylhexyl)-2-methyl-1,2,3-propantriamine dipropionate 100-500 100-500 1.0-100 10-100 N ,N -bis(2-ethylhexyl)-2-methyl-1,2,3-prop triamine tripropionate 100-500 100-500 10-100 10-100 N ,N -biS(2-ethylhexyD-2-methyl-1,2,3-propanetriamine dicaprylate 100-500 100-500 10100 10-100 N ,N bis(Z-ethylhexyl)-2-methy1-1,2,3-propane triamine tricaprylate 100-500 100-500 10-100 l0100 Example 11 Example VII A thefaQefltlc antlfuflgal foot P can be 25 A therapeutic lotion can be formulated as follows: pared by IIllXlIlg 0.5 to 5.0 grams of N ,2-d1methyl-N ,N bis(Z-ethylhexyl)-1,2,3-propanetriamine tricaprylate with Parts 10.0 grams boric acid, 20.0 grams of starch and enough Funglclde of Example I talc to make a 100.0 gram composition. Methyl, cellulose q Glycerin 2.0 Example III Alcohol 10.0 A very fine washable therapeutic ointment can be prei g to make mo'oo pared by mixing 0.5 to 5 .0 grams of N ,2-dimethyl-N ,N r bis(2 ethylhexyl) 1,2,3 propanetriamine tripropionate Evample V1 with enough hydrophilic ointment (USP) to make 100 35 The following compounds also exhibit antifungal characteristics in foot powders, soaps, aerosols, shampoos and ointments: N ,2-dimethyl-N ,N -bis(Z-ethylheXyl)-l,2,3-propanetriamine mono-undecylenate; N ,N bis (Z-ethylhexyl) -2-methyl-1,2,3-propanetriamine monoundecylenate; N ,2 dimethyl N ,N bis(2 ethylhexyl)-1,2,3-propanetriamine mono-propionate; N ,N bis(2-ethylhexyl)-2-methyl-1,2,3-propanetriamine monocaprylate; N ,2-dimethyl-N ,N -bis(2-ethylhexyl)-l,2,3- propanetria'rnine diundecylenate; N ,N bis(2 ethyl hexyl) 2-methyl-l,2,3-propanetriamine triundecylenate; N ,2 dimethyl N ,N bis(2 ethylhexyl) 1,2,3- propanetriamine mono-caprylate; N ,N bis(2 ethylheXyl)2-methyl-1,2,3-propanetriarnine mono-propionate; N52 dimethyl N ,N bis(2 ethylhexyl) 1,2,3- propanetriamine triundecylenate; and N ,N -bis(2-ethylhexyl)-2-methyl-1,2,3-propanetriamine diundecylenate.

It is claimed:

1. A process for treating superficial fungus infections which comprises applying to the skin as the essential antifungal agent a triamine acid salt having the following general formula:

wherein R represents a member selected from the group consisting of hydrogen and methyl, with the proviso that if one R is methyl then the other R must be hydrogen; R represents a member selected from the group consisting of caprylic, propionlc and undecylenic acids, and x is selected from the group consisting of 0 and 1, with the proviso that at least one x is l, in an efiective antifungal amount.

2. The process of claim 1 wherein R is caprylic acid.

3. The process of claim 1 wherein R is propionic acid.

4. The process of claim 1 wherein R is undecylenic acid.

The process of claim 1 wherein said salt is N ,2- dimethyl N ,N bis(2 ethylhexyl) 1,2,3 propanetriamine dipropionate.

6. The process of claim 1 wherein said salt is N ,2- dimethyl N ,N bis(2 ethylhexyl) 1,2,3 propanetriamine tripropionate.

7. The process of claim 1 wherein said salt is N ,2- dimethyl N ,N bis(2 ethylhexyl) 1,2,3 propanetriamine dicaprylate.

8. The process of claim 1 wherein said salt is N ,2- dirnethyl N ,N bis(2 ethylhexyl) 1,2,3 propanetriamine tricaprylate.

9. The process of claim 1 wherein said salt is N ,N his (2 ethylhexyl) 2 methyl 1,2,3 propanetriamine dipropionate.

10. The process of claim 1 wherein said salt is N ,N bis(2 ethylhexyl) 2 methyl 1,2,3 propanetriamine tripropionate.

11. The process of claim 1 wherein said salt is N ,N bis(2 ethylhexyl) 2 methyl 1,2,3 propanetriamine dicaprylate.

12. The process of claim 1 wherein said salt is N ,N bis (2 ethylhexyl) 2 methyl 1,2,3 propanetriamine tricaprylate.

13. A therapeutic anti-fungal composition consisting essentially of a topical carrier and anti-fungal amounts of a triamine acid salt having the following general formula:

wherein R represents a member selected from the group consisting of hydrogen and methyl, with the proviso that if one R is methyl then the other R must be hydrogen; R represents a member selected from the group consisting of caprylic, propionic and undecylenic acids; and x is selected from the group consisting of O and 1, with the proviso that at least one x is 1.

14. The composition of claim 13 wherein the carrier is a foot powder.

15. The composition of claim 13 wherein the carrier is a shampoo.

16. The composition of claim 13 wherein the carrier is an ointment.

17. The composition of claim 13 wherein the carrier is an aerosol.

References Cited UNITED STATES PATENTS 2,290,174 7/1942 Epstein et a1. 167-22 2,436,779 2/1948 Senkus 260404.5 X 2,994,675 8/1961 Haward et al. 260-4045 X 2,998,438 8/1961 Charney et al. 260404.5

ALBERT T. MEYERS, Primary Examiner.

V. C. CLARKE, Assistant Examiner. 

1. A PROCESS FOR TREATING SUPERFICIAL FUNGUS INFECTIONS WHICH COMPRISES APPLYING TO THE SKIN AS THE ESSENTIAL ANTIFUGAL AGENT A TRIAMINE ACID SALT HAVING THE FOLLOWING GENERAL FORMULA: 